Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: Implications for molecular mimicry and cross-recognition among mitochondrial autoantigens

Hirohisa Shigematsu, Shinji Shimoda, Minoru Nakamura, Sho Matsushita, Yasuharu Nishimura, Norihiro Sakamoto, Yasunori Ichiki, Yoshiyuki Niho, M. Eric Gershwin, Hiromi Ishibashi

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Abstract

The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: Group A 170ExDK173 and group B 168ElExD172. 170E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas 173K and 168E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an ElExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vβ in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.

Original languageEnglish (US)
Pages (from-to)901-909
Number of pages9
JournalHepatology
Volume32
Issue number5
StatePublished - 2000

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T-Cell Antigen Receptor Specificity
Molecular Mimicry
Biliary Liver Cirrhosis
Autoantigens
T-Lymphocytes
T-Cell Antigen Receptor
Peptides
Cell Line
dihydrolipoamide succinyltransferase
Clone Cells
Complementarity Determining Regions
T-Lymphocyte Epitopes
Antibody Formation
Anti-Idiotypic Antibodies
Ligands
Antigens
Amino Acids

ASJC Scopus subject areas

  • Hepatology

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Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis : Implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. / Shigematsu, Hirohisa; Shimoda, Shinji; Nakamura, Minoru; Matsushita, Sho; Nishimura, Yasuharu; Sakamoto, Norihiro; Ichiki, Yasunori; Niho, Yoshiyuki; Gershwin, M. Eric; Ishibashi, Hiromi.

In: Hepatology, Vol. 32, No. 5, 2000, p. 901-909.

Research output: Contribution to journalArticle

Shigematsu, Hirohisa ; Shimoda, Shinji ; Nakamura, Minoru ; Matsushita, Sho ; Nishimura, Yasuharu ; Sakamoto, Norihiro ; Ichiki, Yasunori ; Niho, Yoshiyuki ; Gershwin, M. Eric ; Ishibashi, Hiromi. / Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis : Implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. In: Hepatology. 2000 ; Vol. 32, No. 5. pp. 901-909.
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abstract = "The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: Group A 170ExDK173 and group B 168ElExD172. 170E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas 173K and 168E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an ElExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vβ in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.",
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T1 - Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis

T2 - Implications for molecular mimicry and cross-recognition among mitochondrial autoantigens

AU - Shigematsu, Hirohisa

AU - Shimoda, Shinji

AU - Nakamura, Minoru

AU - Matsushita, Sho

AU - Nishimura, Yasuharu

AU - Sakamoto, Norihiro

AU - Ichiki, Yasunori

AU - Niho, Yoshiyuki

AU - Gershwin, M. Eric

AU - Ishibashi, Hiromi

PY - 2000

Y1 - 2000

N2 - The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: Group A 170ExDK173 and group B 168ElExD172. 170E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas 173K and 168E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an ElExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vβ in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.

AB - The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: Group A 170ExDK173 and group B 168ElExD172. 170E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas 173K and 168E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an ElExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vβ in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.

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